This invention relates to an improved method for reducing the severity of asthma and the risk of developing asthma.
Asthma is a chronic inflammatory disorder of the airways in which many cells play a role, including mast cells and eosinophils. In susceptible individuals this inflammation causes symptoms which are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment, and causes an associated increase in airway responsiveness to a variety of stimuli.
Asthma can be inherited, is not contagious and may be chronic and persistent or occurring in the form of attacks which are periodic and usually at least partly reversible. Attacks vary in severity and frequency from person to person. Many factors may contribute to the development of asthma including exposure to inhaled allergens such as pollens, mold spores, house dust mites and animal dander. In an individual who has developed asthma, many stimuli can trigger asthma attacks including allergens, viral respiratory infections (colds or the flu), irritants in the air (smoke, air pollution, perfume), damp, cold weather, and strenuous exercise. In addition, anxiety and emotional stress can bring on and worsen the symptoms of asthma.
During an asthma attack the muscles around the bronchial tubes tighten and the linings of the bronchial tubes swell (become inflamed) and produce thick mucus decreasing the internal diameter of the tubes. These changes block the flow of air making it hard to breathe. When asthma is properly controlled the bronchial tubes are of normal size.
Asthma is a common disease among both children and adults. An estimated 7% of people in the United States have been diagnosed as asthmatic. The corresponding figure for New Zealand is about 10% (Burney, P. et al. 1996 Variations in the Prevalence of Respiratory Symptoms, Self-Reported Asthma Attacks, and Use of Asthma Medication in the European Community Respiratory Health Survey. Eur. Respir. J. 9:687-695). The occurrence of asthma in both Western and developing countries has increased markedly over the last 30 years. This relatively short time frame suggests that environmental rather than genetic factors are at work.
In most cases asthma is an atopic disorder in which the underlying process is due to an allergic response to common environmental allergens. This allergic response is a function of the immune system characterized by activation and recruitment of eosinophils to the lung causing the characteristic chronic swelling and inflammation of the airways that affects the breathing of sufferers.
The pharmaceutical treatment of asthma includes several different classes of drugs, including beta agonists, topical or oral steroids and theophyllines. If used appropriately such treatments may keep asthma symptoms from developing or relieve them when they are present. Beta agonists and theophyllines primarily act by relaxing the muscles surrounding the airways while steroids act to reduce (and even prevent) inflammation and mucus production. Other medications exist and more are being developed due to the growing interest in and concern over the prevalence, morbidity and mortality of asthma worldwide.
Asthma is known to be a disease of the immune system. It is known that the process leading to inflammation of the airways is mediated by the Th2 lymphocytes (Th2s) whose usual function is to act against parasites. These cells secrete the cytokines interleukin-4 (IL-4) and IL-5 leading to enhanced production of immunoglobulin E (IgE) by B cells and the generation and recruitment of eosinophils respectively. Activation of mast cells by allergens releases histamine and other mediating chemicals that trigger an acute inflammatory response, including mucus production intended to flush dying parasites off tissue walls. In asthma the enhanced mucus production merely hinders breathing further. Eosinophils release cytotoxins meant to kill invading parasites but in asthma merely result in inflammation and necrosis of the bronchial epithelium. The increased eosinophil population, localized recruitment and the resultant tissue damage are termed xe2x80x9ceosinophilia.xe2x80x9d
The global increase in atopic disorders such as asthma, hay fever and eczema is inversely correlated with the decline in the extent of exposure to human diseases such as tuberculosis, measles and whooping cough. These diseases all illicit a characteristic Th1 type immune response, mediated by the Th1 lymphocytes (Th1s), which leads to heightened expression of the cytokine interferon-xcex3 (IFN-xcex3), a powerful suppressive mediator of Th2 activity. It has been suggested that the lack of exposure to such Th1 inducing infections increases the risk of developing atopy and that by inducing a Th1 type immune response it is possible to down regulate the Th2 response thus reducing the likelihood of developing atopic disorders such as asthma.
The need exists for an asthma treatment that modulates the immune system to reduce the risk of developing atopy, rather than the traditional treatment of responding with drugs to suppress or alter the symptoms once the disorder has developed or the sufferer is in the midst of an attack. An added benefit would be if such a treatment also has a similar inhibitory effect in a current sufferer of an atopic disorder to reduce the severity of their disease.
It has been shown that among Japanese school children of between 12 and 13 years of age there is a strong inverse correlation between delayed hypersensitivity to Mycobacterium tuberculosis and atopy. Positive tuberculin responses predicted a lower incidence of asthma, lower serum IgE levels and cytokine profiles consistent with a Th1 response. (Shirakawa, T. et al. 1997 The Inverse Association Between Tuberculin Responses and Atopic Disorder. Science 275:77-79).
Another study has shown that early subcutaneous (Bacillus Calmette-Guxc3xa9rin [BCG]) infection in Swedish children with atopic heredity has no preventative effect on the development of atopic disorders before school age. (Alm, J. S. et al. 1997 Early BCG Vaccination and Development of Atopy. The Lancet 350:400-403).
Mycobacterium vaccae infections have been shown to suppress serum IgE and allergen-specific IL-5 synthesis in mice allergic to ovalbumin. (Wang, C. C. and Rook, G. A. W. 1998 Inhibition of an Established Allergic Response to ovalbumin in BALB/c Mice by killed Mycobacterium vaccae. Immunology 93: 307-313.)
U.S. Pat. No. 5,599,545 discloses an adjuvant consisting essentially of killed cells of Mycobacterium vaccae to be used in the immunotherapy of mycobacterial diseases such as tuberculosis and leprosy by promoting the Th1 response.
U.S. Pat. Nos. 5,767,097, 5,721,351 and 5,721,270 disclose various methods for inhibiting the Th2 response. However, they all refer to ways of interfering with an activated Th2 response rather than trying to prevent its activation or mediating it at a causal level.
Therefore it is an object of this invention to provide a method for reducing the risk of the development of asthma in non-sufferers, and for reducing the severity of asthma in sufferers, by stimulating the body""s immune system to suppress the atopic (Th2) immune response.
Accordingly one form of the invention may be said to be a method for reducing the severity of asthma and for reducing the risk of developing asthma, comprising
administering a vaccine
consisting of an immunologically effective dose of Th1 type immune response inducing mycobacteria
to the airways of individuals.
Preferably the vaccine is administered to the respiratory tract.
Preferably the vaccine consists of Mycobacterium bovis (Bacillus Calmette-Guxc3xa9rin [BCG]).
Preferably the vaccine contains xe2x89xa72xc3x97105 colony forming units (CFUs) of mycobacteria.
Preferably the vaccine contains xe2x89xa72xc3x97105 colony forming units (CFUs) of live mycobacteria.
Preferably the vaccine contains xe2x89xa72xc3x97105 colony forming unit (CFU) equivalents of killed mycobacteria.
Preferably the vaccine contains xe2x89xa72xc3x97105 colony forming unit (CFU) equivalents of mycobacterial cell wall components.
Preferably the vaccine contains xe2x89xa72xc3x97105 colony forming unit (CFU) equivalents of mycobacterial cell membrane components.
Preferably the vaccine contains xe2x89xa72xc3x97105 colony forming unit (CFU) equivalents of mycobacterial cell cytoplasm components.
Preferably the vaccine contains xe2x89xa72xc3x97105 colony forming unit (CFU) equivalents of mycobacterial genetic material.
Preferably the vaccine contains xe2x89xa72xc3x97105 colony forming unit (CFU) equivalents of mycobacterial secreted products.